The major histocompatibility complex (MHC) includes a number of genes which control or regulate the immune response. Several genes mapping in the I-region of the MHC appear to control the interaction of immunocompetent cells including the interaction of thymus-derived (T) lymphocytes with bone marrow-derived (B) lymphocytes or macrophages. In the guinea pig there seems to be close association between I-region-associated (Ia) antigens of the MHC and immune response (Ir) genes controlling the T cell-dependent response to certain antigens. The objective to this proposal is to further define the role of MHC antigens in immunocompetent cell interactions and their involvement in the immunogenic interaction with antigens. The functional expression of Ir genes in macrophages will be further examined by two general approaches. First, genetic analyses will be performed to determine if under any circumstances an antigen under Ir gene control can be presented in the context of nonresponder haplotype to responder T cells. In reciprocal experiments, it will be determined if nonresponder T cells can be sensitized to antigen associated with the responder haplotype. A second approach will determine if macrophages "process" antigen to an immunogenic form, and the role of Ia antigens in conventional antigen recognition and/or processing. Recognition of macrophage-associated antigens by T cells will be further defined through the use of antisera directed against antigen-specific T cells to define the recognition structure(s). Efforts will also be made to adapt the findings in the guinea pig model to mice where more extensive genetic analyses may be performed.